Vascular endothelial growth factor and vascular endothelial growth factor receptor complex (VEGF-VEGFR complex) (VEGF-VEGFR complex)

The vascular endothelial growth factor (VEGF) and its receptor (VEGFR) complex is a fundamental signaling unit that regulates the formation and maintenance of the vascular and lymphatic systems (1.1.2, 1.3.1). This complex is formed when ligands such as VEGF-A, VEGF-B, VEGF-C, VEGF-D, or placental growth factor (PlGF) bind to the extracellular domains of their respective tyrosine kinase receptors, primarily VEGFR-1, VEGFR-2, and VEGFR-3 (1.1.1, 1.2.1). Upon ligand binding, the receptors undergo dimerization and autophosphorylation, which triggers intracellular signaling cascades including the PI3K/Akt and MAPK pathways (1.2.3, 1.3.5). These pathways drive essential endothelial cell processes such as proliferation, migration, and survival, as well as increasing vascular permeability (1.1.3, 1.2.4). In pathological conditions, particularly cancer, the overproduction of VEGF by tumor cells leads to excessive angiogenesis, providing the necessary blood supply for tumor growth and metastasis (1.1.2, 1.4.1). Consequently, the VEGF-VEGFR axis has become a major therapeutic target, with drugs like bevacizumab (a neutralizing antibody) and sunitinib (a kinase inhibitor) designed to disrupt this signaling (1.2.2, 1.2.5). Beyond oncology, inhibitors of this complex are widely used to treat ocular diseases characterized by abnormal blood vessel growth, such as age-related macular degeneration (1.2.4, 1.3.2). However, because VEGF signaling is also required for normal vascular homeostasis, these therapies are often associated with systemic side effects like hypertension and proteinuria (1.2.1, 1.3.2).

Other names

VEGF/VEGFR complexVascular permeability factor/receptor complexVEGF-A/VEGFR-2 complexVEGF-C/VEGFR-3 complexVEGF-VEGFR signaling axisVascular endothelial growth factor signaling pathway

Drugs targeting the VEGF-VEGFR complex primarily act through three mechanisms: 1) Neutralization of circulating VEGF ligands by monoclonal antibodies (e.g., bevacizumab) or decoy receptors (e.g., aflibercept) to prevent receptor binding; 2) Competitive inhibition of the extracellular domain of VEGFRs (e.g., ramucirumab); and 3) Inhibition of the intracellular tyrosine kinase domain of VEGFRs by small-molecule inhibitors (e.g., sunitinib, sorafenib) to block autophosphorylation and downstream signaling (1.2.1, 1.2.2, 1.3.2).